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https://hdl.handle.net/2440/60698
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Type: | Journal article |
Title: | Shiga toxin 2 and Flagellin from Shiga-toxigenic Escherichia coli superinduce interleukin-8 through synergistic effects on host stress-activated protein kinase activation |
Author: | Jandhyala, D. Rogers, T. Kane, A. Paton, A. Paton, J. Thorpe, C. |
Citation: | Infection and Immunity, 2010; 78(7):2984-2994 |
Publisher: | Amer Soc Microbiology |
Issue Date: | 2010 |
ISSN: | 0019-9567 1098-5522 |
Statement of Responsibility: | Dakshina M. Jandhyala, Trisha J. Rogers, Anne Kane, Adrienne W. Paton, James C. Paton and Cheleste M. Thorpe |
Abstract: | Shiga toxins expressed in the intestinal lumen during infection with Shiga-toxigenic Escherichia coli must translocate across the epithelium and enter the systemic circulation to cause systemic (pathological) effects, including hemolytic uremic syndrome. The transepithelial migration of polymorphonuclear leukocytes in response to chemokine expression by intestinal epithelial cells is thought to promote uptake of Stx from the intestinal lumen by compromising the epithelial barrier. In the present study, we investigated the hypothesis that flagellin acts in conjunction with Shiga toxin to augment this chemokine expression. We investigated the relative contributions of nuclear factor B (NF-B) and mitogen-activated protein kinase (MAPK) signaling to transcription and translation of interleukin-8. Using reporter gene constructs, we showed that flagellin-mediated interleukin-8 gene transcription is heavily dependent on both NF-B and extracellular signal-regulated kinase 1 and 2 (ERK-1/2) activation. In contrast, inhibition of p38 has no detectable effect on interleukin-8 gene transcription, even though flagellin-mediated activation of host p38 is critical for maximal interleukin-8 protein expression. Inhibition of MAPK-interacting kinase 1 suggests that p38 signaling affects the posttranscriptional regulation of interleukin-8 protein expression induced by flagellin. Cotreatment with Stx2 and flagellin results in a synergistic upregulation of c-Jun N-terminal protein kinases (JNKs), p38 activation, and a superinduction of interleukin-8 mRNA. This synergism was also evident at the protein level, with increased interleukin-8 protein detectable following cotreatment with flagellin and Stx2. We propose that flagellin, in conjunction with Shiga toxin, synergistically upregulates stress-activated protein kinases, resulting in superinduction of interleukin-8 and, ultimately, absorption of Stx into the systemic circulation. |
Keywords: | Cell Line Humans Escherichia coli Infections Mitogen-Activated Protein Kinases Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinase 3 p38 Mitogen-Activated Protein Kinases Flagellin NF-kappa B Interleukin-8 Fluorescent Antibody Technique, Indirect Enzyme-Linked Immunosorbent Assay Cloning, Molecular Reverse Transcriptase Polymerase Chain Reaction Signal Transduction Enzyme Activation Shiga Toxin 2 Shiga-Toxigenic Escherichia coli |
Rights: | Copyright © 2010, American Society for Microbiology. All Rights Reserved |
DOI: | 10.1128/IAI.00383-10 |
Published version: | http://dx.doi.org/10.1128/iai.00383-10 |
Appears in Collections: | Aurora harvest Molecular and Biomedical Science publications |
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